Discovery of novel c-Met kinase inhibitors bearing a thieno[2,3-d]pyrimidine or furo[2,3-d]pyrimidine scaffold

Bioorg Med Chem. 2011 Jul 1;19(13):3906-18. doi: 10.1016/j.bmc.2011.05.038. Epub 2011 May 24.

Abstract

A series of thieno[2,3-d]pyrimidines and furo[2,3-d]pyrimidines were synthesized and evaluated for the c-Met inhibition. Thieno[2,3-d]pyrimidine 6b stood out as the most potent showing an IC(50) of 35.7 nM. This compound displayed high inhibitory effect on cell proliferation in BaF3-TPR-Met cells and showed high selectivity for c-Met family against other 14 tested kinases. However, compound 6b was found ineffective in the c-Met-dependent U-87MG human gliobastoma xenograft model that may be relevant to its poor PK profile.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Drug Evaluation, Preclinical
  • Glioblastoma / drug therapy
  • Humans
  • Mice
  • Mice, Nude
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / metabolism
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / therapeutic use
  • Structure-Activity Relationship
  • Thiophenes / chemistry*
  • Thiophenes / pharmacokinetics
  • Thiophenes / therapeutic use
  • Transplantation, Heterologous

Substances

  • N-(3-fluoro-4-(5-phenylthieno(2,3-d)pyrimidin-4-yloxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Thiophenes
  • Proto-Oncogene Proteins c-met
  • pyrimidine